Inhibitors of HIV-1 reverse transcriptase are central to anti-HIV therapy.1 Though there are five FDA-approved drugs in the non-nucleoside class,2 efavirenz (1) and rilpivirine (2) are particularly important as they are components of the one-a-day combination therapies Atripla and Complera.3 The other two components of the pills are the same, emtricitabine and tenofovir, which are in the nucleoside class of HIV-RT inhibitors. The goal of our research has been to discover new non-nucleoside inhibitors (NNRTIs) that may incorporate advantages for administration, formulation, diminished side effects, and activity towards variant strains of the virus.
For example, issues with efavirenz include its daily dosage of 600 mg, poor activity towards HIV-1 variants containing the commonly occurring Lys103Asn (K103N) mutation in RT, and neurological side effects. The situation with rilpivirine is curious. Although it has much superior performance in cell-based assays that efavirenz, more virological failure is observed for patients using Complera than Atripla.3,4 Another unusual feature of rilpivirine is its extremely low aqueous solubility (0.02 μg/ml)5 in comparison to the typical range of 4-4000 μg/ml for oral drugs.6

The challenges in developing new NNRTIs that represent an advance over existing compounds are great. One seeks simultaneously compounds that embody high potency towards the wild-type (WT) virus and numerous clinically observed variants, good pharmacological properties including solubility, an absence of structural features that may lead to rapid metabolism, and avoidance of toxicities stemming from reactive functional groups or metabolic products.7,8

A particularly promising class of NNRTIs that we have developed is catechol diethers including 3 and 4.9 3 appears to be the most potent anti-HIV agent ever reported with an EC50 of 0.055 nM in the standard MT-2 cell assay using wild-type HIV-1. The difluoro analog 4 is also extremely potent at 0.32 nM, has good potency towards variant strains containing the Y181C (16 nM) and K103N/Y181C (85 nM) mutations, and shows low cytotoxicity towards the T-cells (CC50=45 μM). It was also possible to obtain X-ray crystal structures of 3 and 4 in complex with WT HIV-RT.10 Thus, further structure-based design activities in the catechol diether series have a firm foundation.
A structural feature in 3 and 4 as well as in rilpivirine that is addressed here is the cyanovinyl (CV) group. For most medicinal chemists viewing these structures, concern arises that the CV group may be sufficiently electrophilic to act as a “Michael acceptor” leading to potential covalent modification of proteins, nucleic acids, or other biological entities. Though in reality unsaturated nitriles are poor Michael acceptors that require reactive organometallic nucleophiles to undergo conjugate additions,11 the fact is almost no approved drugs contain a cyanovinyl group, and lack of precedent is often taken as a warning sign in drug discovery. When a search is done for a C═C—C≡N substructure in a comprehensive file containing the structures of ca. 1900 approved oral drugs,12 there are just five hits: rilpivirine, entacapone, nilvadipine, teriflunomide, and trilostane. For the latter two examples, the substructure only arises as a tautomer of an α-cyanoketone. Rilpivirine is unique in incorporating a simple CV group. By contrast, non-vinyl cyano groups are generally considered to be acceptable in drugs;13 there are 36 examples in the database.
Thus, we set out to find a replacement for the cyanovinyl group in the catechol diethers.